The endothelial lining of blood vessels is highly diversified. Many, perhaps all, normal tissues put a tissue-specific “signature” on their vasculature, and tumor vessels differ from normal vessels both in morphology and molecular composition (Ruoslahti, 2002). Tumors induce angiogenesis to accommodate the growth of the tumor (Hanahan and Weinberg, 2000) and many of the changes in tumor vessels are angiogenesis-related (Brooks et al., 1994; Christian et al., 2003; Ferrara and Alitalo, 1999; Pasqualini et al., 2000). Moreover, tumor blood vessels have tumor type-specific and, in some stages, stage-specific characteristics; in vivo screening of phage libraries yielded distinct sets of homing peptides selectively recognizing angiogenic signatures in two transgenic mouse models of organ specific tumorigenesis. Homing peptides can also distinguish the angiogenic blood vessels of pre-malignant lesions from those of fully malignant lesions in the same tumor model (Hoffman et al., 2003; Joyce et al., 2003), indicating that vascular changes mirror the stage of tumor development.
The lymphatic system constitutes a second vascular system, one that has only an efferent arm. Tumors frequently induce lymphangiogenesis, as well as co-opt existing lymphatics (Cao et al., 2004; Cassella and Skobe, 2002; Stacker et al., 2002). Tumors may contain intratumoral lymphatics, but, more commonly, an extensive network of lymphatic vessels is present around tumor tissue (Jackson et al., 2001; Laakkonen et al., 2002; Padera et al., 2002). The lymphatics within tumors, when present, are generally non-functional in fluid transport (Padera et al., 2002), possibly reflecting compression by interstitial pressure and blockade by intra-luminal tumor cells. The lymphatic vessels in and around tumors are an important conduit of metastasis. Indeed, growth factor-stimulated enhancement of lymphatic vessel expression in tumors increases metastasis (Mandriota et al., 2001; Skobe et al., 2001). Conversely, inhibiting lymphangiogenesis suppresses lymphatic metastasis, but generally does not affect tumor growth (Saharinen et al., 2004).
As disclosed herein, tumor lymphatics, like tumor blood vessels, express specific markers, and that these lymphatic markers are tumor type-specific and distinct from blood vessel markers in the same tumors. Thus, needed in the art are compositions and methods for that selectively bind tumor lymphatics or lymphatics in pre-malignant lesions for use in early detection and tumor targeting.